Synergistic effects of 15-deoxy-Δ12, 14-prostaglandin J2 and anticancer agents on renal cell carcinomas

[Speaker] Tomonari Fujita:1
[Co-author] Yui Asanoma:1, Wakana Shirai:1, Ena Hashimoto:1, Tomoki Echigo:1, Yuri Yoneda:2, Hiroaki Kumagai:2, Hiromi Koma:2, Yasuhiro Yamamoto:2, Tatsurou Yagami:2
1:Hyogo Prefectural Kobe High School, Japan, 2:Himeji Dokkyo University, Japan

BACKGROUND: The responsiveness of renal cell carcinomas (RCCs) to conventional anticancer drugs is lower than those of other cancer cell lines. 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) is known as an endogenous anticancer substance. Previously, we have reported that 15d-PGJ2 activated caspase-3, condensed chromatin and induced apoptosis in RCCs independently of its nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, synergistic effects of 15d-PGJ2 and various anticancer agents on RCCs have not yet been sufficiently elucidated.
METHODS AND RESULTS: In the presence of serum, we examined effects of various anticancer agents on Caki-2 cells. We evaluated antitumor activities by MTT-reducing activity, caspase-3 activity, chromatin condensation and propidium iodide uptake. Anticancer activities of bortezomib (proteasome inhibitor), paclitaxel (microtubule polymer stabilizer), camptothecin (topoisomerase I inhibitor), etoposide (topoisomerase II inhibitor) and doxorubicin (topoisomerase II inhibitor) were detected in Caki-2 cells. RCCs. 15d-PGJ2 significantly enhanced the cytotoxicity of topoisomerase inhibitors (camptothecin, etoposide and doxorubicin), but not those of bortezomib and paclitaxel. 15d-PGJ2 and topoisomerase inhibitors activated caspase 3 by themselves. Combination of 15d-PGJ2 with topoisomerase inhibitors elevated the level of caspase 3 activity synergistically. In addition, 15d-PGJ2 increased the etoposide-condensed chromatin synergistically. A PPARγ antagonist, GW9662, did not block these synergistic effects of 15d-PGJ2 and topoisomerase inhibitors on Caki-2 cells.
CONCLUSION: In the present study, we confirmed the antitumor effect of paclitaxel on Caki-2 cells. To our knowledge, we provided the first evidence that bortezomib induced cell death in Caki-2 cells. Furthermore, we demonstrated that 15d-PGJ2 enhanced the antitumor activity of topoisomerase inhibitors against RCC independently from PPARγ.

Advanced Search